One evening at Herrington High School in Ohio, several teachers and the principal leave after discussions about the school's budget. Having left her keys behind, Principal Valerie Drake (Bebe Neuwirth) returns to retrieve them. In her office, she is barred from leaving by Coach Willis (Robert Patrick), who becomes increasingly erratic. As she attempts to leave, Willis impulsively stabs a pencil through her hand. Valerie flees to the entrance only to find the door chained up and the drama teacher Mrs. Olsen (Piper Laurie) is outside. She retrieves her keys and grabs a pair of scissors, and is able to escape. Outside, Mrs. Olsen emotionlessly grabs the scissors, and stabs Valerie to death.
The following morning, the film's six protagonist students are introduced.
Casey Connor (Elijah Wood), the dedicated but perpetually klutzy and harassed geek photographer for the school newspaper.
The spiteful Delilah Profitt (Jordana Brewster), the paper's editor-in-chief and head cheerleader.
Delilah's mistreated boyfriend Stan Rosado (Shawn Hatosy) who is contemplating quitting the school's football team to pursue academics.
Zeke Tyler (Josh Hartnett), an intelligent yet rebellious student repeating his senior year who sells, among other illegal items, a powdery ecstasy-like drug he manufactures and distributes. Zeke is confronted by the timid Miss Elizabeth Burke (Famke Janssen), who expresses concern for him over his illegal activities.
A naive transfer student from Atlanta, Georgia, Marybeth Louise Hutchinson (Laura Harris), attempts to befriend self-styled outcast, Stokely Mitchell (Clea DuVall), despite the fact that Delilah has deliberately spread rumors that Stokes is a lesbian even though she has a crush on Stan. Marybeth, on the other hand, develops a crush on Zeke.
While eating lunch on the football field, Casey notices a strange creature in the grass. He takes it to science teacher Mr. Furlong (Jon Stewart), where the specimen is examined and believed to be a new species of cephalopod-specific parasite called a mesozoan.
Delilah takes Casey into the teacher's lounge to find a story for the front page, where they hide in a closet. They witness Coach Willis and Ms. Olsen assault the school nurse, Ms. Harper (Salma Hayek) by forcing one of the creatures into her ear. They also find the body of Mrs. Brummel (Susan Willis). Casey and Delilah flee, and Casey calls the police. Principal Drake claims nothing is wrong and that Casey is seeking attention.
The next day, Casey tells Delilah, Stan and Stokely that he believes the teachers are being controlled by aliens. After Zeke and Marybeth enter the classroom and tease them about their theory, Mr. Furlong confronts them. Furlong suddenly becomes defensive and attempts to infect them. Zeke cuts off Furlong's fingers and then injects his homemade drugs into Furlong's eye, apparently killing him.
Zeke takes the five to his house where he examines and experiments with Casey's specimen. He discovers that it needs water to survive and can be killed by his drugs because it is a diuretic. Zeke makes everyone take some of his drug to prove they are human and unaffected. Delilah is revealed as infected, and she destroys Zeke's lab and most of his drug supply before escaping.
Acting on Stokely's speculation that killing the queen alien would revert everyone to normal, the group returns to the school that evening, where their football team is playing a game and infecting opposing players. Believing Principal Drake to be the queen, they isolate her in the gym and fatally shoot her. Stan goes outside and confronts the coach and football team to see if it worked, but gets infected.
Zeke and Casey go to Zeke's car to retrieve more of Zeke's drugs. Casey leads infected students away from Zeke, who encounters Miss Burke in the parking lot and seemingly kills her when he makes his escape.
Back at the gym, Stokely becomes suspicious of Marybeth during a conversation about pretending to be what one isn't. Marybeth subsequently reveals herself to be the alien queen. Earlier, she faked taking the drug. Casey and Stokely flee to the swimming pool where Stokely gets injured and becomes infected. Zeke and Casey hide in the locker room, where Marybeth reverts to her human disguise, naked. She explains that she is taking over Earth because her own planet is dying. Marybeth transforms back into her true form and hurls Zeke across the room into several lockers, knocking him out. Casey seizes the drug and tricks the queen into following him into the retracting bleachers, thus trapping her. Casey then stabs the drug into the queen's eye. The queen infects Casey with her dying breath, but Casey almost immediately returns to normal upon the queen's death. The dead body of the alien queen dissolves into powdered remains. Casey returns to the locker room and finds Stokely and Zeke alive.
One month later, everyone has returned to normal. Stan and Stokely begin dating, and Zeke takes Stan's place on the football team (while Miss Burke affectionately watches him practice). Mr. Furlong has miraculously survived the attack, now sporting an eyepatch and bandages on his hand. Casey begins dating Delilah and has been considered a local hero.